The primary mission of the SRA is to understand the basic biological mechanisms, genetic and physiological risk factors, predictive diagnostic biomarkers, and potential methods of preventing sudden unexpected death, the most common cause of premature mortality in human epilepsy. This project will test the principal hypothesis that mutation of single genes co-expressed in brain, heart, and brainstem central autonomic neurons increase SUDEP risk by promoting cardiorespiratory arrhythmias. We will identify and validate novel ictal bradycardia and SUDEP gene candidates in mouse models to expand the SUDEP risk genome, and use modifier genes that suppress this risk in forebrain and brainstem autonomic circuits to genetically dissect critical SUDEP pathways. We will examine molecular excitability mechanisms perturbed by these genes in brain and heart, and the role of seizures and hypoxia in pathological network depolarization. We will also explore translational pharmacologic and genetic rescue strategies in these models. These findings will contribute to future genetic risk profiling for SUDEP in clinical exomes and point to new gene-directed approaches to reduce SUDEP in patients at high risk.